Induced-fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design

Abstract

Crystal structures of acetylcholinesterase complexed with ligands are compared with side-chain conformations accessed by native acetylcholinesterase in molecular dynamics (MD) simulations. Several crystallographic conformations of a key residue in a specific binding site are accessed in a simulation of native acetylcholinesterase, although not seen in rotomer plots. Conformational changes upon ligand binding thus involve preexisting equilibrium dynamics. Consequently, rational drug design could benefit significantly from conformations monitored by MD simulations of native targets.

Figure 1.

3D structure of native TcAChE (PDB access code 1ea5). Catalytic-triad residues are in red, the active-site gorge in green, and PAS Trp279 and CAS Trp84 in blue.

Figure 2.

χ₁ and χ₂ angles of Trp279 side-chain conformations from simulation, X-ray crystallography, and a rotomer library. (A) Conformations from a 20-ns MD simulation (gray dots) and 89 crystallographic AChE structures deposited in the PDB (black triangles). Simulated conformations form five islands. The white pentacle indicates the conformation in the crystal structure (1ea5) that the simulation is based on. Experimental conformations fall in seven groups: a, most native and complex structures; b, native DmAChE (Harel et al. 2000) (1QO9); c, TcAChE/tacrine (Harel et al. 1993) (1ACJ); d, mAChE/TZ2PA6syn (Bourne et al. 2004) (1Q83); e, mAChE/HI-6 (Ekstrom et al. 2006) (2GYU), mAChE/HLO-7 (2JEY), and mAChE/HLO-7/tabun (monomer A, 2JEZ) complexes; f, TcAChE/A7 (Rydberg et al. 2006) (2CKM), TcAChE/A8 (Rydberg et al. 2006) (1ODC), TcAChE/NF595 (Colletier et al. 2006) (2CEK), mAChE/obidoxime (Ekstrom et al. 2006) (2GYW), and mAChE/HLO-7/tabun (monomer B, 2JEZ) complexes; g, mAChE/ortho-7 (Ekstrom et al. 2006) (2GYV) and mAChE/ortho-7/tabun (2JF0) complexes. (B) Most favorable conformations predicted by PROCHECK (Laskowski et al. 1993) based on an experimental library of rotomers (gray areas). The same experimental conformations as in A are presented (black triangles and white pentacle).

Figure 3.

Time dependence of χ₁ and χ₂ along the 20-ns trajectory. Colored bars indicate the five islands shown in Figure 2A. Khaki: island containing crystallographic groups a and b; blue: island containing group c; cyan: island containing group d; gray: island containing group f; mauve: island containing group g.